Process for producing an anti-depressant effect with piperazine quinolines

ABSTRACT

IN WHICH R IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF H AND CH3 AND CH3 AND NONTOXIC PHARMACOLOGICALLY ACCEPTABLE ACID ADDTION SALTS THEREOF. THE COMPOUND MAY BE COMBINED WITH ACCETABLE PHARMACEUTICAL VEHICLES TO FORM COMPOSITIONS FOR ADMINISTRATION.   2-(4-R-PIPERAZINO)QUINOLINE   AN ANTI-DEPRESSANT EFFECT IS PRODUCED IN AN ORGANISM BY ADMINISTERING AN ANTI-DEPRESSANT EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:

United States Patent Office 3,629,418 Patented Dec. 21, 1971 PROCESS FOR PRODUCING AN ANTI-DEPRES- SANT EFFECT WITH PIPERAZINE QUINOLINES Rodolfo Rodriguez, Tlalpan County, Mexico, assignor to Miles Laboratories, Inc., Eikhart, Ind. No Drawing. Filed Feb. 14, 1969, Ser. No. 799,508 Int. Cl. A61k 27/00 US. Cl. 424-250 3 Claims ABSTRACT OF THE DISCLOSURE An anti-depressant effect is produced in an organism by administering an anti-depressant effective amount of a compound of the formula:

in which R is a member selected from the group consisting of H and CH and nontoxic pharmacologically acceptable acid addition salts thereof. The compound may be combined with acceptable pharmaceutical vehicles to form compositions for administration.

This invention relates to a novel process for producing an anti-depressant effect in an organism. More particularly, this invention relates to a process for producing an antidepressant effect in a warm blooded animal by the administration to such animal of an anti-depressant effective amount of a compound of the formula:

W in which R is H or CH, or nontoxic pharmacologically acceptable acid addition salts thereof. The invention also has reference to a new composition comprising the compound and a pharmaceutical vehicle for use in alleviating depressant states.

Although the treatment of depressant states with medicinal preparations is not new, it isonly within the last few years that emphasis has been placed on the development of drugs for effectively alleviating this condition. A number of drugs have been found effective in relieving depressant states through a variety of actions, such as through stimulation of the central nervous system or through a supressant effect. Among the commonly utilized medications are monoamino oxidase inhibitors, such as iproniazid, nialamide; tricyclic compounds, such as imipramine, amitryptyline; and amphetamine-like compounds, such as amphetamine sulfate, methamphetamine and methylphenidate. These drugs appear to be effective in treating endogenous depression and may be useful in treating the depressive phase of certain types of schizophrenia.

While the known compositions are effective in producing anti-depressant activity, each is subject to certain decided disadvantages. Thus, hepatic toxicity, including jaundice, has been reported in association with the use of monoamine oxidase inhibitors, atropine-like side effects are frequently observed with the tricyclic compounds, and excessive central nervous system stimulation is a main limitation for the amphetamines.

Depression has been said to vary as much as pain and like pain is one of mans most common ailments. Unfortunately, in spite of many attempts to categorize depressive illness, no satisfactory classification has yet been devised. With such difiiculty in identification of cause, site and mode of action, an anti-depressant drug is similarly difficult to identify.

Therefore, it is an object of this invention to provide a new process for producing an anti-depressant effect in an organism.

Another object of this invention is to provide a process for producing an anti-depressant effect using a new active ingredient that does not display the disadvantages associated with the known anti-depressant compositions.

A further object of this invention is to provide a novel medication comprising the active ingredient and a pharmaceutical vehicle therefor.

The invention is embodied in a novel process for producing an anti-depressant effect in an organism by administering to such organism an anti-depressant effective amount of a compound of the structural Formula I:

in which R is a member selected from the group consisting of H and CH or nontoxic pharmacologically acceptable acid addition salts thereof.

The invention also embodies a novel composition of a therapeutically effective quantity of said compound or nontoxic pharmacologically acceptable additional salts thereof and a pharmaceutical vehicle therefor.

The active ingredient of the medication used for the novel process of the invention is selected from the group having the structural formula:

follows N NH onooon i ,-N NH I:

N oncoon Although Z-bromoquinoline has been utilized in this general equation, other Z-haloquinolines, such as 2-ch1oroquinoline, may be similarly used with equally desirable results.

The active ingredient used in the novel process of this invention may be in the form of the free base and is preferably in the form of a nontoxic pharmacologically acceptable acid addition salt thereof. These acid addition salts may be prepared from mineral acids such as halogen acids or sulfuric acid, or organic acids such as citric acid, maleic acid and other similar acids. Additional examples of the preparation of these acids will be presented in the subsequent detailed examples.

Medications may be prepared for use in the novel process of this invention including, as an active ingredient, at least one of the compounds of Formula I. These medications may be conveniently prepared by combining the active ingredient with a pharmaceutical vehicle having components selected from the fillers, carriers, extenders, excipients and the like, generally used in pharmaceutical formulations. Medications may be prepared in the solid state as tablets or capsules or in the liquid state as suspensions or solutions. Similar dosage forms suitable for oral, parenteral, intramuscular, subcutaneous, intravenous or other convenient routes of administration may also be provided. The pharmaceutical vehicle may also include common diluents or tableting adjuncts such as cellulose powder, corn starch, magnesium stearate, calcium sulfate, talc and such, used according to accepted pharmaceutical manufacturing practices. Unit dosages (a specific weight, such as mg. or g.) of active ingredient in a medication may be varied so that an adequate amount is present to provide the desired therapeutic dose which produces a particular therapeutic effect Without untoward side effects. Unit dosages of between about 1 and mg. per capsule are beneficially used for oral administration of the medication. Vials containing a sterile preparation for parenteral administration are beneficially prepared with the unit dosage of about 10 mg. per vial.

The therapeutic dose, administered using the unit dosages described above, will depend upon the depressive state of the patient. Depression tends to be cyclic in nature and varying in severity. Therefore, the therapeutic dose must be individualized according to the need of each patient. Beneficially, initial daily doses ranging between about 3 and 60 mg. per day are considered safe and readily indicative of a required therapeutic dose.

The invention will be further understood by reference to the following examples which are provided as illustrations and are not intended to be construed as limitations upon the invention which is properly set forth in claims appended hereto. These examples are divided into two general groups, the first drawn to the preparation of the active ingredients and the second to pharmacology related to the process of the invention.

EXAMPLE 1 1-(2-quinolyl)piperazine A mixture of 2-chloroquinoline (477 g., 2.92 moles), piperazine (503 g., 5.83 moles) and 750 ml. of toluene was stirred and heated under reflux for 6 hours. The mixture was cooled in an ice bath and 750 ml. of water was added with stirring. Then the mixture was acidified with concentrated hydrochloric acid. The insoluble 1,4- bis-(2-quinolyl)piperazine was removed by filtering the slightly warm mixture through Celite. The filtrate was diluted with 2 liters of water which dissolved most of the solid which had separated out. The toluene layer was separated and the aqueous portion was extracted with a little ether. Then the aqueous mixture was treated with decolorizing charcoal and filtered through Celite. The solution was made alkaline with sodium hydroxide. The solid free base was collected on a filter and washed with water. The crude material was dissolved in about 1 liter of hot ethanol and the solution was clarified with charcoal. Then the mixture was diluted with 2 liters of water. The white crystals which separated on cooling were collected, washed with water and dried in an oven at 150 F. The 1-(2-quinolyl)piperazine (437 g., 70.2 percent) melted at 8183 C.

Analysis.Calcd. for C H N (percent): N (basic), 13.14; N (total), 1970. Found (percent): N (basic), 12.93; N (total), 19.72.

4 EXAMPLE 2 1-(2-quinolyl)piperazine maleate The free base was dissolved in 4200 ml. of hot 2- propanol and a solution of maleic acid (239 g., 2.06 moles) in 1500 ml. of hot 2-propanol was added in one portion with stirring. The stirring was continued, while the mixture was cooled in an ice bath. Then the salt was collected, washed with 2-propanol and dried in the oven at 150 F. The 1-(2-quinolyl)piperazine maleate amounted to 650 g. (95.8 percent based on the free base) and melted at 174175 C.

Analysis.Calcd. for C H N O (percent): N (basic), 8.51; N (total), 12.76; N.E., 164.7. Found (percent): N (basic), 850; N (total), 12.70; N.E., 165.3.

EXAMPLE 3 2- (4-methyl-1-piperazinyl) quinoline A mixture of 2-chloroquinoline (81.8 g., 0.5 mole), l-methylpiperazine (100.2 g., 1 mole) and ml. of toluene was heated to boiling. An exothermic reaction set in, but it was necessary to apply additional heat to maintain a vigorous boiling. After about 30 minutes the spontaneous reaction was over, and the mixture was heated under reflux for 2 hours longer. A dark syrupy material separated out.

The mixture was stirred and cooled, during which 300 ml. of water containing 100 ml. of concentrated hydrochloric acid was added. A small amount of insoluble solid material was removed by filtration and washed with ether and water. The aqueous portion of the filtrate and washings was separated and clarified with charcoal. An excess of a saturated aqueous solution of sodium hydroxide was added to the filtrate. The free base was collected, washed with water and dried at 50 C. The crude product (104.5 g. 95%) melted at 111 C.

The crude free base was dissolved in hot ethanol, and the solution was clarified with charcoal. The filtrate and washings were concentrated by evaporation and diluted with hot water to incipient cloudiness. The crystals which formed on cooling and scratching were collected, washed with Water and dried at 100 C. The cream-colored free base (102 g., 90%) melted at 111112 C.

Analysis.Calcd. for C14H17N3 (percent): N (basic) 6.16. Found (percent): N, (basic), 6.08.

EXAMPLE 4 2- (4-methyl-Lpiperazinyl) quinoline maleate 2-(4-methyl-1-piperazinyl)quinoline (101.0 g., 0.445 mole) in 300 ml. of hot 2-propanol was treated with a solution of maleic acid (53.6 g., 0.46 mole) in 200 ml. of hot 2-propanol. Crystals began to form immediately. After cooling in an ice bath the crystals were collected, washed with ethyl acetate and dried at 100 C. The crude salt (146.0 g., M.P. 161 C.) was dissolved in about 2 liters of boiling 2-propanol. The solution was concentrated by evaporation until crystals began to form. The mixture was cooled and the salt was collected. The crystals were washed with ethyl acetate and dried at 100 C. The product amounted to 141.5 g. (93%).

Analysis.Calcd. for c14, H17N3'C4H4O4 (percent): N (basic) 8.16; N (total), 12.24; N.E., 171.7. Found (percent): N (basic), 8.14; N (total), 12.32; N.E., 173.3.

EXAMPLE 5 The anti-depressant activity of the active ingredient of the medication used in the novel process of this invention was assessed by its ability to antagonize the ptotic effect of reserpine in mice. The test was performed substantially as described by Chen and Bohner: J. Pharmac. Esp. Ther. 131: 179, 1961. A group of mice were randomly selected from a larger group weighing between about 22 and 35 grams. Each animal received intraperitoneally 4 mg./kg. of reserpine in a 5% ascorbic acid solution. Three hours after the reserpine injection aqueous solutions including TABLE 1 Dose, Anti-resperine Active ingredient ing/kg. activity 3.1 Potent. 1-(2-quin0ly1)piperzine maleate 10. Do.

31.0 Very potent.

3.1 Potent. 2-(4methyl-1-piperazinyl)-quiuo1ine maleate 10. 0 Do.

31.0 Very potent.

Imipramine 5-(3-dimethylaminopropyl)-10, 10.0 Weak.

ll-dihydro-EH-dibenz-[b,flazepine. 31.0 Potent.

100.0 Very potent.

EXAMPLE 6 Toxicity of the active ingredients used in this invention was determined by administering each active ingredient in graduated doses orally to separate groups of mice and rats and observing the animals reactions. A control compound, imipramine, was also administered according to the same procedure. The observed results of the toxicity test are presented in the following Table 2 in which active ingredient 1-(2-quino1yl)piperazine maleate is designated A and active ingredient 2-(4-methyl-1-piperazinyl)quinoline maleate is designated B.

sufficient motor impairment to block a response to the stimuli used, the motor function of the animals was assessed with a rotarod test. In this test, rats were trained to walk for periods of 100 seconds on a wooden rod (2 inches in diameter) rotating at 13 r.p.m. The active ingredients used in this invention were administered as set forth in Example 7 except that larger doses were utilized until motor impairment was observed. Imipramine was also administered in the same manner as a control drug. The observed results of the rotarod test are set forth in the following Table 3. The specificity of the anti-muricidal effect was measured by calculating the ratio of the rotarod ED to the anti-muricide ED A ratio significantly greater than 1 indicates a specific anti-muricidal effect at nondebilitating doses. The active ingredients were observed as highly specific anti-muricidal agents as the ratio of rotarod ED to anti-muricidal ED was substantially in excess of 1, i.e., 6.2 and 13.5. For the control drug, imipramine, a ratio of about 1.5 was determined.

What is claimed is:

1. A process of producing an anti-depressant effect in a depressed warm-blooded animal comprising administering to said warm-blooded animal an anti-depressant effective amount of a compound of the formula:

TABLE 2 Animals, Dosage Days LD 50 confidence Compound Species Sex No./g1'oup groups held limits) 10 6 14 223 mg./kg.(210.6236.1). 10 6 14 200mg./kg.(179.3223.5). 10 7 14 233.5 mg./kg. (2095-2385). 10 7 14 188.5mg./kg. 1828-1945). 10 5 14 450 mg./kg.(233868). 10 5 14 560 mg./k .(459-683). 5 5 14 620 Ing./kg. (501-762) 5 5 14 717 mg./kg. (590-367) 5 5 14 290 mg./kg.(228368) 5 5 14 330 m ./kg.(2s4-383).

EXAMPLE 7 The potential anti-depressant activity of the active ingredients used in the invention was also assessed by ob- 50 serving its effect upon the muricide tendency of killer rats. The procedure followed was substantially the same as that set forth by Horovitz et al., Int. J. Neuropharmacol. 5:405, 1966. According to this procedure the mouse killing blocking ability of the active ingredients was evaluated in a group of killer rats. Twenty five killing rats of both sexes were used to evaluate each of the active ingredients. At weekly intervals, the active ingredient was administered intraperitoneally in varying doses and muricide responses observed at 15 minute intervals after the injection. Imipramine was administered and observed in the same manner as a standard. The observed results of this example are set forth in Table 3.

EXAMPLE 8 To determine if the action of the active ingredients of the invention was anti-depressant in nature or if there was in which R is H or CH or nontoxic pharmacologically acceptable acid addition salts thereof.

2. The process of claim 1 in which said compound is 1-(2-quinolyl)piperazine.

3. The .process of claim 1 in which said compound is 2- (4-methyl-1-piperazinyl) quinoline.

References Cited Chem. Abst. (I), 65, 6100(b), 1966.

Chem. Abst. (II), 68, Subj. Index PZ, p. 3273 (1968).

Chem. Abst. (III), 68, 20736(b) (1968).

Chem. Abst. (IV), 51, Subj. Index, P-Z, p. 2068 (1957).

STANLEY J. FRIEDMAN, Primary Examiner 

